The Program Project Grant focuses on Integrative Neurobiology of Cardiovascular Regulation. It has represented the major scientific emphasis of the Cardiovascular Research Center at Iowa since 1971. The strength of this competitive renewal, now it its 30th year is based on the stability, productivity and cohesion of its senior leadership and the continuous effort to link molecular biology to integrative neurobiology and mechanisms of cardiovascular disease. The application has seven projects one less than the current program. Three of the seven projects address the central neural control of the circulation, two examine the reflex control from baroreceptors and cardiac sensory afferents, and two examine neurovascular mechanisms. The three central neural control projects are: the project by A.K. Johnson on the mechanisms of the alarming increase in morbidity and mortality from cardiac disease associated with depression; the project by Davisson/Sigmund on the functional significance of the selective regional and cellular activation of the brain renin-angiotensin system; and the project by Felder on the CNS effects of immune system activation (cytokines) in myocardial infarction-heart failure causing increased sympathetic drive. The two reflex control projects are: the project by Abboud/Benson/Welsh on the molecular determinants of mechanotransduction in baroreceptors and mechano- and proton-sensitivity of cardiac sensory afferents in myocardial ischemia and failure; and the project by Chapleau/Hoshi on the differential mechanisms of baroreflex dysfunction in atherosclerosis and aging mediated by reactive oxygen species. The two projects on neurovascular mechanisms are: the project by Haynes/Mark on vascular consequences of sympathetic neural activation in human obesity, and the project by Russo/Faraci/Heistad which is an extension of the important work on CGRP in subarachnoid hemorrhage exploring novel molecular mechanisms for enhancing the expression of CGRP receptors in the trigeminovascular system of cerebral vessels. In addition to the Administration Core, the Imaging/Immunocytochemistry Core and the Transgenic and Vector Cores are already providing invaluable service to the existing programs. The technical approaches are state-of the-art, the animals models are well established, the work is mechanistic and the concepts are innovative. The relevance to morbid and fatal disease such as depression and myocardial infarction, heart failure, hypertension, atherosclerosis, stroke and obesity is direct. We expect the scientific outcome to be far greater than the sum of the components.